Methyl-CpG targeted transcriptional activation allows re-expression of tumor suppressor genes in human cancer cells.
DNA methylation and histone modifications are both major features of the epigenetic silencing seen at tumor suppressor genes (TSGs) in cancer. DNA methylation inhibitors, but not, in general, histone deacetylase, can reactivate TSGs. However, DNA methylation inhibitors frequently upregulate genes whose promoters remain unmethylated. Herein we demonstrated that the methyl-CpG targeted transcriptional activation (MeTA), which allows re-expression of TSGs without DNA demethylation, is widely seen in human cancer. We further analyzed MeTA and found that transcriptional coactivators are recruited at hypermethylated promoter regions of TSGs using the methyl-CpG binding domain (MBD). Reactivation of MLH1 by MeTA accompanied acetylation of histone H3 lysine 9/14 at the promoter region. Furthermore, all ten genes analyzed in three cell lines were reactivated by the effect of MeTA. Our present results lead to an efficient way to search for transcriptionally silenced genes with highly methylated CpG islands, particularly TSGs in cancer and developmentally important genes in embryonic stem cells.
Fukushige
Shinichi
S
Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. Electronic address: shinichi@mail.tains.tohoku.ac.jp.
Kondo
Emiko
E
Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
Horii
Akira
A
Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D003841:Deoxycytidine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D003841:Deoxycytidine; D000070957:MutL Protein Homolog 1; D001374:Azacitidine